Gene Essentiality Profiling Reveals Gene Networks and Synthetic Lethal Interactions with Oncogenic Ras
Open accessAbstract
The genetic dependencies of human cancers widely vary. Here, we catalog this heterogeneity and use it to identify functional gene interactions and genotype-dependent liabilities in cancer. By using genome-wide CRISPR-based screens, we generate a gene essentiality dataset across 14 human acute myeloid leukemia (AML) cell lines. Sets of genes with correlated patterns of essentiality across the lines reveal new gene relationships, the essential substrates of enzymes, and the molecular functions of uncharacterized proteins. Comparisons of differentially essential genes between Ras-dependent and -independent lines uncover synthetic lethal partners of oncogenic Ras. Screens in both human AML and engineered mouse pro-B cells converge on a surprisingly small number of genes in the Ras processing and MAPK pathways and pinpoint PREX1 as an AML-specific activator of MAPK signaling. Our findings suggest general strategies for defining mammalian gene networks and synthetic lethal interactions by exploiting the natural genetic and epigenetic diversity of human cancer cells.
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Genome-wide CRISPR screens identified RCE1, ICMT, SHOC2, RAF1, ERK, RSK1, and PREX1 as synthetic lethal with mutant KRAS.
“These included two processing enzymes involved in membrane targeting, RCE1 and ICMT, as well as RAS pathway members including SHOC2, RAF1, ERK, RSK1, and PREX1 [112].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [112]
The Results section, “Two Independent Screening Approaches Reveal Common Synthetic Lethal Interactions with Oncogenic Ras” (page unavailable), identifies RCE1, ICMT, RAF1, SHOC2, and PREX1 as selectively required in Ras-dependent AML lines; it also reports strong scores for MAPK1 (ERK) and RPS6KA1 (RSK1). The claim is too specific to mutant KRAS: the screens included NRAS-mutant lines, MAPK1 was dispensable in some mutant-Ras lines, and the Results section on PREX1 says its selective essentiality was confined to mutant-Ras AML among the cancer types tested. (LLM, conf=0.88)
Experimental — accuracy not yet measuredDownstream effectors of KRAS signaling mutated post-KRAS inhibition included activating lesions in PIK3CA, MEK1, BRAF, and RAF1.
“The downstream effectors of KRAS signaling that were mutated post-KRAS inhibition included activating lesions in PIK3CA, MEK1, BRAF, and RAF1 [51,68,97,112].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [112]
The Results sections on synthetic-lethal interactions and PREX1 identify MAPK-pathway dependencies and show that an experimentally introduced active MEK1 mutant bypassed dependence on upstream components. They do not report activating lesions in PIK3CA, MEK1, BRAF, or RAF1 arising after KRAS inhibition. Searches for post-inhibition mutations and resistance found no passage addressing that claim. (LLM, conf=0.76)
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Subramanian, A., Tamayo, P., Mootha, V. K., Mukherjee, S., Ebert, B. L., Gillette, M. A., Paulovich, A., Pomeroy, S. L., Golub, T. R., Lander, E. S., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0506580102 · Cited by 53,625 · see citing works
Self-citationMultiplex Genome Engineering Using CRISPR/Cas Systems
Cong, L., Ran, F. A., Cox, D., Lin, S., Barretto, R., Habib, N., Hsu, P. D., Wu, X., Jiang, W., Marraffini, L. A., et al. (2013) · Science · doi:10.1126/science.1231143 · Cited by 15,339 · see citing works
The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity
Barretina, J., Caponigro, G., Stransky, N., Venkatesan, K., Margolin, A. A., Kim, S., Wilson, C. J., Lehár, J., Kryukov, G. V., Sonkin, D., et al. (2012) · Nature · doi:10.1038/nature11003 · Cited by 7,950 · see citing works
Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy
Farmer, H., McCabe, N., Lord, C. J., Tutt, A. N. J., Johnson, D. A., Richardson, T. B., Santarosa, M., Dillon, K. J., Hickson, I., Knights, C., et al. (2005) · Nature · doi:10.1038/nature03445 · Cited by 6,683 · see citing works
Genome-scale CRISPR-Cas9 knockout screening in human cells
Shalem, O., Sanjana, N. E., Hartenian, E., Shi, X., Scott, D. A., Mikkelsen, T. S., Heckl, D., Ebert, B. L., Root, D. E., Doench, J. G., et al. (2014) · Science · doi:10.1126/science.1247005 · Cited by 5,234 · see citing works
Functional profiling of the Saccharomyces cerevisiae genome
Giaever, G., Chu, A. M., Ni, L., Connelly, C., Riles, L., Véronneau, S., Dow, S., Lucau-Danila, A., Anderson, K., André, B., et al. (2002) · Nature · doi:10.1038/nature00935 · Cited by 4,316 · see citing works
Discovery and saturation analysis of cancer genes across 21 tumour types
Lawrence, M. S., Stojanov, P., Mermel, C. H., Robinson, J. T., Garraway, L. A., Golub, T. R., Meyerson, M., Gabriel, S. B., Lander, E. S., & Getz, G. (2014) · Nature · doi:10.1038/nature12912 · Cited by 3,096 · cited 2× · see citing works
“An Integrative Genomic Approach Reveals Oncogene Dependency Cancer genome sequencing efforts have provided an increasingly complete catalog of the genes altered during tumor development (Lawrence et al., 2014).”
Self-citationGenome-Scale CRISPR-Mediated Control of Gene Repression and Activation
Gilbert, L. A., Horlbeck, M. A., Adamson, B., Villalta, J. E., Chen, Y., Whitehead, E. H., Guimaraes, C., Panning, B., Ploegh, H. L., Bassik, M. C., et al. (2014) · Cell · doi:10.1016/j.cell.2014.09.029 · Cited by 2,728 · see citing works
Systematic identification of genomic markers of drug sensitivity in cancer cells
Garnett, M. J., Edelman, E. J., Heidorn, S. J., Greenman, C. D., Dastur, A., Lau, K. W., Greninger, P., Thompson, I. R., Luo, X., Soares, J., et al. (2012) · Nature · doi:10.1038/nature11005 · Cited by 2,456 · see citing works
Drugging the undruggable RAS: Mission Possible?
Cox, A. D., Fesik, S. W., Kimmelman, A. C., Luo, J., & Der, C. J. (2014) · Nature Reviews Drug Discovery · doi:10.1038/nrd4389 · Cited by 1,997 · see citing works
Identification and characterization of essential genes in the human genome
Wang, T., Birsoy, K., Hughes, N. W., Krupczak, K. M., Post, Y., Wei, J. J., Lander, E. S., & Sabatini, D. M. (2015) · Science · doi:10.1126/science.aac7041 · Cited by 1,617 · see citing works
Self-citationKoike-Yusa, H., Li, Y., Tan, E.-P., Velasco-Herrera, M. D. C., & Yusa, K. (2014) · Nature Biotechnology · doi:10.1038/nbt.2800 · Cited by 1,064 · see citing works
The CASTOR Proteins Are Arginine Sensors for the mTORC1 Pathway
Chantranupong, L., Scaria, S. M., Saxton, R. A., Gygi, M. P., Shen, K., Wyant, G. A., Wang, T., Harper, J. W., Gygi, S. P., & Sabatini, D. M. (2016) · Cell · doi:10.1016/j.cell.2016.02.035 · Cited by 843 · see citing works
Self-citationMany roads lead to oncogene-induced senescence
Courtois-Cox, S., Jones, S. L., & Cichowski, K. (2008) · Oncogene · doi:10.1038/sj.onc.1210950 · Cited by 397 · see citing works
Blasco, R. B., Francoz, S., Santamaría, D., Cañamero, M., Dubus, P., Charron, J., Baccarini, M., & Barbacid, M. (2011) · Cancer Cell · doi:10.1016/j.ccr.2011.04.002 · Cited by 302 · see citing works
Rodriguez-Viciana, P., Oses-Prieto, J., Burlingame, A., Fried, M., & McCormick, F. (2006) · Molecular Cell · doi:10.1016/j.molcel.2006.03.027 · Cited by 215 · see citing works
C-Raf Is Required for the Initiation of Lung Cancer by K-RasG12D
Karreth, F. A., Frese, K. K., DeNicola, G. M., Baccarini, M., & Tuveson, D. A. (2011) · Cancer Discovery · doi:10.1158/2159-8290.cd-10-0044 · Cited by 149 · see citing works
Flagged first, then by citations
Research works printed but not linked: 45
- Aguirre AJ Meyers RM Weir BA Vazquez F Zhang C-Z Ben-David U Cook A Ha G Harrington WF Doshi MB 2016 Genomic copy number dictates a gene-independent cell response to CRISPR-Cas9 targeting Cancer Disc http://dx.doi.org/10.1158/2159-8290.CD-16-0154 PMC4972686 27260156 · DOI
- Ashworth A Lord CJ Reis-Filho JS 2011 Genetic interactions in cancer progression and treatment Cell 145 30 38 21458666
- Barbie DA Tamayo P Boehm JS Kim SY Moody SE Dunn IF Schinzel AC Sandy P Meylan E Scholl C 2009 Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1 Nature 462 108 112 19847166 PMC2783335
- Bassi DE Fu J Lopez de Cicco R Klein-Szanto AJP 2005 Pro-protein convertases: “master switches” in the regulation of tumor growth and progression Mol Carcinog 44 151 161 16167351
- Berger AH Brooks AN Wu X Shrestha Y Chouinard C Piccioni F Bagul M Kamburov A Imielinski M Hogstrom L 2016 High-throughput Phenotyping of Lung Cancer Somatic Mutations Cancer Cell 30 214 228 27478040 PMC5003022
- Boehm JS Hahn WC 2011 Towards systematic functional characterization of cancer genomes Nat Rev Genet 12 487 498 21681210
- Chen C Itakura E Weber KP Hegde RS de Bono M 2014 An ER complex of ODR-4 and ODR-8/Ufm1 specific protease 2 promotes GPCR maturation by a Ufm1-independent mechanism PLoS Genet 10 e1004082 24603482 PMC3945108
- Cheung HW Cowley GS Weir BA Boehm JS Rusin S Scott JA East A Ali LD Lizotte PH Wong TC 2011 Systematic investigation of genetic vulnerabilities across cancer cell lines reveals lineage-specific dependencies in ovarian cancer Proc Natl Acad Sci USA 108 12372 12377 21746896 PMC3145679
- Chow HY Jubb AM Koch JN Jaffer ZM Stepanova D Campbell DA Duron SG O’Farrell M Cai KQ Klein-Szanto AJP 2012 p21-Activated kinase 1 is required for efficient tumor formation and progression in a Ras-mediated skin cancer model Cancer Res 72 5966 5975 22983922 PMC3500416
- Cordeddu V Di Schiavi E Pennacchio LA Ma’ayan A Sarkozy A Fodale V Cecchetti S Cardinale A Martin J Schackwitz W 2009 Mutation of SHOC2 promotes aberrant protein N-myristoylation and causes Noonan-like syndrome with loose anagen hair Nat Genet 41 1022 1026 19684605 PMC2765465
- Costanzo M VanderSluis B Koch EN Baryshnikova A Pons C Tan G Wang W Usaj M Hanchard J Lee SD 2016 A global genetic interaction network maps a wiring diagram of cellular function Science 353 pii: aaf1420 PMC5661885 27708008
- Cowley GS Weir BA Vazquez F Tamayo P Scott JA Rusin S East-Seletsky A Ali LD Gerath WFJ Pantel SE 2014 Parallel genome-scale loss of function screens in 216 cancer cell lines for the identification of context-specific genetic dependencies Sci Data 1 140035 25984343 PMC4432652
- Ebi H Costa C Faber AC Nishtala M Kotani H Juric D Della Pelle P Song Y Yano S Mino-Kenudson M 2013 PI3K regulates MEK/ERK signaling in breast cancer via the Rac-GEF, P-Rex1 Proc Natl Acad Sci USA 110 21124 21129 24327733 PMC3876254
- Feig LA Cooper GM 1988 Relationship among guanine nucleotide exchange, GTP hydrolysis, and transforming potential of mutated ras proteins Mol Cell Biol 8 2472 2478 3043178 PMC363447
- Floyd BJ Wilkerson EM Veling MT Minogue CE Xia C Beebe ET Wrobel RL Cho H Kremer LS Alston CL 2016 Mitochondrial protein interaction mapping identifies regulators of respiratory chain function Mol Cell 63 621 632 27499296 PMC4992456
- Forbes SA Beare D Gunasekaran P Leung K Bindal N Boutselakis H Ding M Bamford S Cole C Ward S 2015 COSMIC: exploring the world’s knowledge of somatic mutations in human cancer Nucleic Acids Res 43 D805 D811 25355519 PMC4383913
- Garraway LA Lander ES 2013 Lessons from the cancer genome Cell 153 17 37 23540688
- Gibson DG Young L Chuang RY Venter JC Hutchison CA 3rd Smith HO 2009 Enzymatic assembly of DNA molecules up to several hundred kilobases Nat Methods 6 343 345 19363495
- Hart T Chandrashekhar M Aregger M Steinhart Z Brown KR MacLeod G Mis M Zimmermann M Fradet-Turcotte A Sun S 2015 High-resolution CRISPR screens reveal fitness genes and genotype-specific cancer liabilities Cell 163 1515 1526 26627737
- Horlbeck MA Gilbert LA Villalta JE Adamson B Pak RA Chen Y Fields AP Park CY Corn JE Kampmann M Weissman JS 2016 Compact and highly active next-generation libraries for CRISPR-mediated gene repression and activation eLife 5 e19760 27661255 PMC5094855
- Hughes TR Marton MJ Jones AR Roberts CJ Stoughton R Armour CD Bennett HA Coffey E Dai H He YD 2000 Functional discovery via a compendium of expression profiles Cell 102 109 126 10929718
- Kaelin WG Jr 2005 The concept of synthetic lethality in the context of anti-cancer therapy Nat Rev Cancer 5 689 698 16110319
- Kim HS Mendiratta S Kim J Pecot CV Larsen JE Zubovych I Seo BY Kim J Eskiocak B Chung H 2013 Systematic identification of molecular subtype-selective vulnerabilities in non-small-cell lung cancer Cell 155 552 566 24243015 PMC3836195
- King AJ Sun H Diaz B Barnard D Miao W Bagrodia S Marshall MS 1998 The protein kinase Pak3 positively regulates Raf-1 activity through phosphorylation of serine 338 Nature 396 180 183 9823899
- Klijn C Durinck S Stawiski EW Haverty PM Jiang Z Liu H Degen-hardt J Mayba O Gnad F Liu J 2015 A comprehensive transcriptional portrait of human cancer cell lines Nat Biotechnol 33 306 312 25485619
- Komatsu M Chiba T Tatsumi K Iemura S Tanida I Okazaki N Ueno T Kominami E Natsume T Tanaka K 2004 A novel protein-conjugating system for Ufm1, a ubiquitin-fold modifier EMBO J 23 1977 1986 15071506 PMC404325
- Lehrbach NJ Ruvkun G 2016 Proteasome dysfunction triggers activation of SKN-1A/Nrf1 by the aspartic protease DDI-1 eLife 5 e17721 27528192 PMC4987142
- Luo J Emanuele MJ Li D Creighton CJ Schlabach MR Westbrook TF Wong KK Elledge SJ 2009a A genome-wide RNAi screen identifies multiple synthetic lethal interactions with the Ras oncogene Cell 137 835 848 19490893 PMC2768667
- Luo J Solimini NL Elledge SJ 2009b Principles of cancer therapy: oncogene and non-oncogene addiction Cell 136 823 837 19269363 PMC2894612
- Marcotte R Brown KR Suarez F Sayad A Karamboulas K Krzyza-nowski PM Sircoulomb F Medrano M Fedyshyn Y Koh JLY 2012 Essential gene profiles in breast, pancreatic, and ovarian cancer cells Cancer Discov 2 172 189 22585861 PMC5057396
- Munoz DM Cassiani PJ Li L Billy E Korn JM Jones MD Golji J Ruddy DA Yu K McAllister G 2016 CRISPR screens provide a comprehensive assessment of cancer vulnerabilities but generate false-positive hits for highly amplified genomic regions Cancer Discov 6 900 913 27260157
- Quentmeier H Reinhardt J Zaborski M Drexler HG 2003 FLT3 mutations in acute myeloid leukemia cell lines Leukemia 17 120 124 12529668
- Quentmeier H MacLeod RAF Zaborski M Drexler HG 2006 JAK2 V617F tyrosine kinase mutation in cell lines derived from myeloproliferative disorders Leukemia 20 471 476 16408098
- Radhakrishnan SK den Besten W Deshaies RJ 2014 p97-dependent retrotranslocation and proteolytic processing govern formation of active Nrf1 upon proteasome inhibition eLife 3 e01856 24448410 PMC3896944
- Schlabach MR Luo J Solimini NL Hu G Xu Q Li MZ Zhao Z Smogorzewska A Sowa ME Ang XL 2008 Cancer proliferation gene discovery through functional genomics Science 319 620 624 18239126 PMC2981870
- Starita LM Young DL Islam M Kitzman JO Gullingsrud J Hause RJ Fowler DM Parvin JD Shendure J Fields S 2015 Massively parallel functional analysis of BRCA1 RING domain variants Genetics 200 413 422 25823446 PMC4492368
- Swarthout JT Lobo S Farh L Croke MR Greentree WK Deschenes RJ Linder ME 2005 DHHC9 and GCP16 constitute a human protein fatty acyltransferase with specificity for H- and N-Ras J Biol Chem 280 31141 31148 16000296
- Toledo CM Ding Y Hoellerbauer P Davis RJ Basom R Girard EJ Lee E Corrin P Hart T Bolouri H 2015 Genome-wide CRISPR-Cas9 screens reveal loss of redundancy between PKMYT1 and WEE1 in glioblastoma stem-like cells Cell Rep 13 2425 2439 26673326 PMC4691575
- Trapnell C Roberts A Goff L Pertea G Kim D Kelley DR Pimentel H Salzberg SL Rinn JL Pachter L 2012 Differential gene and transcript expression analysis of RNA-seq experiments with TopHat and Cufflinks Nat Protoc 7 562 578 22383036 PMC3334321
- Tsang YH Dogruluk T Tedeschi PM Wardwell-Ozgo J Lu H Espitia M Nair N Minelli R Chong Z Chen F 2016 Functional annotation of rare gene aberration drivers of pancreatic cancer Nat Commun 7 10500 26806015 PMC4737758
- Tzelepis K Koike-Yusa H De Braekeleer E Li Y Metzakopian E Dovey OM Mupo A Grinkevich V Li M Mazan M 2016 A CRISPR dropout screen identifies genetic vulnerabilities and therapeutic targets in acute myeloid leukemia Cell Rep 17 1193 1205 27760321 PMC5081405
- Wang T Wei JJ Sabatini DM Lander ES 2014 Genetic screens in human cells using the CRISPR-Cas9 system Science 343 80 84 24336569 PMC3972032
- Welch HCE Coadwell WJ Ellson CD Ferguson GJ Andrews SR Erdjument-Bromage H Tempst P Hawkins PT Stephens LR 2002 P-Rex1, a PtdIns(3,4,5)P3- and Gbetagamma-regulated guanine-nucleotide exchange factor for Rac Cell 108 809 821 11955434
- Whitesell L Lindquist SL 2005 HSP90 and the chaperoning of cancer Nat Rev Cancer 5 761 772 16175177
- Whyte DB Kirschmeier P Hockenberry TN Nunez-Oliva I James L Catino JJ Bishop WR Pai JK 1997 K- and N-Ras are geranylger-anylated in cells treated with farnesyl protein transferase inhibitors J Biol Chem 272 14459 14464 9162087
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Hart, T., Tong, A. H. Y., Chan, K., Van Leeuwen, J., Seetharaman, A., Aregger, M., Chandrashekhar, M., Hustedt, N., Seth, S., Noonan, A., et al. (2017) · G3 Genes|Genomes|Genetics · doi:10.1534/g3.117.041277 · Cited by 599 · see citing works
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Papke, B., & Der, C. J. (2017) · Science · doi:10.1126/science.aam7622 · Cited by 399 · see citing works
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Lindeboom, R. G. H., Vermeulen, M., Lehner, B., & Supek, F. (2019) · Nature Genetics · doi:10.1038/s41588-019-0517-5 · Cited by 327 · see citing works
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Kuscu, C., Parlak, M., Tufan, T., Yang, J., Szlachta, K., Wei, X., Mammadov, R., & Adli, M. (2017) · Nature Methods · doi:10.1038/nmeth.4327 · Cited by 344 · see citing works
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Shamloo, B., & Usluer, S. (2019) · Cancers · doi:10.3390/cancers11081178 · Cited by 336 · see citing works
Mapping the Genetic Landscape of Human Cells
Horlbeck, M. A., Xu, A., Wang, M., Bennett, N. K., Park, C. Y., Bogdanoff, D., Adamson, B., Chow, E. D., Kampmann, M., Peterson, T. R., et al. (2018) · Cell · doi:10.1016/j.cell.2018.06.010 · Cited by 319 · see citing works
Muir, A., Danai, L. V., Gui, D. Y., Waingarten, C. Y., Lewis, C. A., & Vander Heiden, M. G. (2017) · eLife · doi:10.7554/elife.27713 · Cited by 311 · see citing works
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Costanzo, M., Kuzmin, E., van Leeuwen, J., Mair, B., Moffat, J., Boone, C., & Andrews, B. (2019) · Cell · doi:10.1016/j.cell.2019.01.033 · Cited by 241 · see citing works
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Epistasis-driven identification of SLC25A51 as a regulator of human mitochondrial NAD import
Girardi, E., Agrimi, G., Goldmann, U., Fiume, G., Lindinger, S., Sedlyarov, V., Srndic, I., Gürtl, B., Agerer, B., Kartnig, F., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-19871-x · Cited by 123 · see citing works
Young, L. C., Hartig, N., Boned del Río, I., Sari, S., Ringham-Terry, B., Wainwright, J. R., Jones, G. G., McCormick, F., & Rodriguez-Viciana, P. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1720352115 · Cited by 98 · see citing works
Paralog buffering contributes to the variable essentiality of genes in cancer cell lines
De Kegel, B., & Ryan, C. J. (2019) · PLOS Genetics · doi:10.1371/journal.pgen.1008466 · Cited by 92 · see citing works
Synthetic Lethal Vulnerabilities in <i>KRAS</i>-Mutant Cancers
Aguirre, A. J., & Hahn, W. C. (2018) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a031518 · Cited by 90 · see citing works
Synthetic Lethal Interaction of SHOC2 Depletion with MEK Inhibition in RAS-Driven Cancers
Sulahian, R., Kwon, J. J., Walsh, K. H., Pailler, E., Bosse, T. L., Thaker, M., Almanza, D., Dempster, J. M., Pan, J., Piccioni, F., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.08.090 · Cited by 90 · see citing works
A multi-scale map of cell structure fusing protein images and interactions
Qin, Y., Huttlin, E. L., Winsnes, C. F., Gosztyla, M. L., Wacheul, L., Kelly, M. R., Blue, S. M., Zheng, F., Chen, M., Schaffer, L. V., et al. (2021) · Nature · doi:10.1038/s41586-021-04115-9 · Cited by 82 · see citing works
Oncogenic KRAS blockade therapy: renewed enthusiasm and persistent challenges
Tang, D., Kroemer, G., & Kang, R. (2021) · Molecular Cancer · doi:10.1186/s12943-021-01422-7 · Cited by 80 · see citing works
Surface antigen-guided CRISPR screens identify regulators of myeloid leukemia differentiation
Wang, E., Zhou, H., Nadorp, B., Cayanan, G., Chen, X., Yeaton, A. H., Nomikou, S., Witkowski, M. T., Narang, S., Kloetgen, A., et al. (2021) · Cell Stem Cell · doi:10.1016/j.stem.2020.12.005 · Cited by 66 · see citing works
KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance
Ash, L. J., Busia-Bourdain, O., Okpattah, D., Kamel, A., Liberchuk, A., & Wolfe, A. L. (2024) · Current Oncology · doi:10.3390/curroncol31040150 · Cited by 59 · see citing works
“Quiescence can lead to insensitivity to drugs targeting essential growth pathways, as these pathways become less critical in dormant cells [115].”
BackgroundDisease Association and Druggability of WD40 Repeat Proteins
Song, R., Wang, Z.-D., & Schapira, M. (2017) · Journal of Proteome Research · doi:10.1021/acs.jproteome.7b00451 · Cited by 45 · see citing works
Sparse dictionary learning recovers pleiotropy from human cell fitness screens
Pan, J., Kwon, J. J., Talamas, J. A., Borah, A. A., Vazquez, F., Boehm, J. S., Tsherniak, A., Zitnik, M., McFarland, J. M., & Hahn, W. C. (2022) · Cell Systems · doi:10.1016/j.cels.2021.12.005 · Cited by 37 · see citing works
Process for an efficient lentiviral cell transduction
Pirona, A. C., Oktriani, R., Boettcher, M., & Hoheisel, J. D. (2020) · Biology Methods and Protocols · doi:10.1093/biomethods/bpaa005 · Cited by 31 · see citing works
- Authors
- Wang, T., Yu, H., Hughes, N. W., Liu, B., Kendirli, A., Klein, K., Chen, W. W., Lander, E. S., & Sabatini, D. M.
- Affiliations
- Broad Institute (US)
- Corresponding author
- Lander, Eric S.
- Sabatini, David M.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2017-02
- Volume
- 168
- Issue
- 5
- Pages
- 890-903.e15
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC5445660
- OpenAlex
- W2584033231
- Cited by
- 632
- References
- 17
- Citations by year
- 2026: 22 · 2025: 34 · 2024: 50 · 2023: 56 · 2022: 81 · 2021: 84 · 2020: 96 · 2019: 80 · 2018: 76 · 2017: 52
- FWCI
- 34.75
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH (CA103866, F31 CA189437)
- National Human Genome Research Institute (2U54HG003067-10)
- MIT Whitaker Health Sciences Fund
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Keywords
- gene essentiality, synthetic lethality, oncogenic Ras, acute myeloid leukemia, gene networks, CRISPR screen, MAPK signaling, P-Rex1, gene dependency, cancer cell lines, pro-B cells
- MeSH terms
- Animals, Carrier Proteins, Humans, Protein Processing, Post-Translational, Leukemia, Myeloid, Acute, ras Proteins, Genes, Essential, MAP Kinase Signaling System, Mitochondrial Proteins, Epigenesis, Genetic, Cell Line, Tumor, Mice, Gene Regulatory Networks, Clustered Regularly Interspaced Short Palindromic Repeats
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